tbuckley/cabot-search huggingface dataset:
Aluminium phthalocyanine–mediated photodynamic therapy promotes antitumour activity in oesophageal cancer stem cells.
Authors: Onyisi Christiana Didamson, Rahul Chandran, Heidi Abrahamse
Journal: Journal of Clinical Oncology (2023)

e15194 Background: Photodynamic therapy (PDT), a non-invasive treatment modality, has emerged as an effective treatment measure for various cancers, including oesophageal cancer. PDT has attracted much attention in the field of oncology due to its low toxicity profile and the selective accumulation of the photoactivated agent in the tumour cells. However, the therapeutic effect of Aluminium (III) Phthalocyanine Chloride Tetra sulfonic Acid (AlPcS 4 Cl) mediated PDT on oesophageal CSCs is limited. In this study, we evaluated the cellular localization of AlPcS 4 Cl and its PDT anticancer effects on oesophageal CSCs. Methods: An in vitro experimental design was employed in this study. Oesophageal cancer (HKESC-1 cells) was grown, and the CSCs were isolated using the magnetic-activated cell sorting (MACS). The isolated CSCs were characterised using a flow cytometry, Hoechst efflux side population test, and immunofluorescence. The CSCs were maintained in a serum-free culture medium and incubated at 37° C, 5% CO 2 and 85% humidity. The cells were grouped into control and experimental groups. The CSCs received two-fold increasing concentrations of AlPcS 4 Cl and were exposed to irradiation at 673.2nm wavelength using a diode laser. After 24 hours post-PDT, the anticancer activities of AlPcS 4 Cl on oesophageal CSCs were examined. The MTT cell viability assay was used to determine the 50% inhibitory concentration (IC50), light microscopy for morphological changes, and adenosine triphosphate (ATP) assay for cell proliferation, lactate dehydrogenase (LDH) assay for cellular toxicity. While cellular localization of AlPcS 4 Cl was examined using fluorescent microscopy. All experimental and control cells were conducted in six biological replicates (n = 6). Results: Results were compiled, and statistical analysis was performed using GraphPad Prism (v5). The mean values of experimental groups were compared with the mean value of the control cells. One-way ANOVA was employed, and a p-value of less than 0.05 was considered statistically significant. Findings from cellular localization showed that the AlPcS 4 Cl is localized in the mitochondria and lysosomes, indicating a probable cellular death pathway. The dose-response of AlPcS 4 Cl on oesophageal CSCs showed an IC50 value of 4µM, suggesting the photosensitizer is efficient for the treatment of CSCs at low concentrations. The CSCs exposed to PDT showed remarkable morphological distortion, high cytotoxic activity, decreased viable cells and significant antiproliferative potential. Conclusions: This study showed that AlPcS 4 Cl promote PDT anticancer effects on oesophageal CSCs and could serve as an efficient therapeutic option for eradicating oesophageal CSCs.
A phase 1 dose escalation trial of ex-vivo expanded allogeneic cord blood–derived natural killer cell immunotherapy for pediatric solid tumor malignancies.
Authors: Sajad Khazal, Jonathan Benjamin Gill, Jessica Foglesong, Sireesha Yedururi, Ajaykumar Morani, Dawen Sui, Roland L. Bassett, Suzanne Gettys, Priti Tewari, Kris Mahadeo, Richard Greg Gorlick, Elizabeth J. Shpall, Katy Rezvani, Najat C. Daw
Journal: Journal of Clinical Oncology (2023)

2546 Background: Despite aggressive multimodality therapy, survival outcomes of most patients with recurrent/refractory solid tumors remain dismal. Preclinical data have shown that natural killer (NK) cells play a significant role in controlling cancer progression, metastasis, and survival. In this phase I dose escalation trial, we evaluated the safety and phase 2 recommended dose of cord blood derived NK cells in children and young adults with recurrent/refractory pediatric solid tumors. Methods: Eligible patients were 1-40 years old. Cord blood donors were 4, 5, or 6/6 HLA matched. Ex-vivo, antigen presenting cell-mediated expansion of human cord blood derived NK cells was performed over 14 days. All patients received lymphodepleting regimen with cyclophosphamide (500 mg/m 2 /day) and etoposide (100 mg/m 2 /day) for 5 days (days -7 to -3) followed by 2 days rest and a single infusion of NK cells on Day 0. The study evaluated two dose levels using a standard 3+3 phase I trial design with an expansion cohort at the maximum tolerated dose. Results: Twelve patients (median age 16 years) received NK cells infusions. Tumor types included osteosarcoma (n = 7), Ewing sarcoma (n = 4), and synovial sarcoma (n = 1). Three patients received NK cells at dose level 1 (5 X 10 7 /Kg), and nine patients at dose level 2 (1 X10 8 /Kg), which was determined to be the recommended Phase 2 dose. No dose-limiting toxicities were observed. Most adverse events were grade 1 and 2 (fatigue, dizziness, nausea and vomiting). Most frequently observed grade 3 and 4 adverse events were leukopenia, neutropenia, lymphopenia, and thrombocytopenia. No cytokine release syndrome or neurotoxicity was observed. Allogeneic NK cells were detected in recipients’ peripheral blood as high as 100% of all NK cell populations and as late as 9 days post infusion. Of the 9 patients evaluable for tumor response, 3 patients (with osteosarcoma) had stable disease and 6 had progressive disease. Conclusions: Allogeneic ex-vivo expanded NK cells immunotherapy demonstrated favorable safety profile in patients with advanced pediatric solid tumors. Strategies to improve efficacy are warranted including using adjuvant therapy to increase persistence, more stringent selection strategies and gene editing approaches to increase alloreactivity against recipient tumor cells. Clinical trial information: NCT03420963 .
Neoadjuvant tislelizumab, a PD-1 mAb plus nab-paclitaxel (nab-P) followed by tislelizumab plus epirubicin/cyclophosphamide (EC) for triple-negative breast cancers (TNBC): Interim analysis of clinical response in a phase 2 TREND trial.
Authors: Yingying Xu, Qiang Zhang, Bo Zhu, Mozhi Wang, Litong Yao
Journal: Journal of Clinical Oncology (2023)

e14623 Background: Chemo-based immunotherapy improves the prognosis of TNBC. However, the dominant population and optimal chemo-backbone of neoadjuvant immunotherapy remain undefined. Aim of TREND trial was to assess the efficacy and safety of tislelizumab in combination with nab-P and EC (nab-P-EC) in neoadjuvant therapy of TNBC. Methods: In this prospective, single-arm phase 2 clinical study, untreated TNBC patients who have clinically node-positive or at least T2 disease without distant metastasis were eligible. Before surgery, enrolled patients received tislelizumab (200 mg IV Q3W) plus weekly nab-P (100 mg/m² IV Q3W) for 12 weeks, followed by tislelizumab (200 mg IV Q3W) plus epirubicin (75 mg/m² IV Q3W) and cyclophosphamide (600 mg/m² IV Q3W) for the subsequently 12 weeks. The primary endpoint was pCR (ypT0/Tis ypN0) and secondary endpoints was objective response rate (ORR, RECIST v1.1). Combined positive score (CPS) of PD-L1 expression in pre-treatment biopsy samples was tested by PD-L1 IHC 22C3 PharmDx. Single-cell RNA sequencing, single-cell TCR sequencing, mass cytometry by time of flight, whole exome sequencing, RNA-seq and olink-assay were performed on pre- and post-treatment samples from primary tumors, metastatic lymph nodes and peripheral blood. Results: Of 43 enrolled patients from Nov 2020 to Nov 2022, 21 patients completed neoadjuvant therapy and accepted surgery in per protocol set (PPS; median age 48 years; range 25-69 years), and 16 were still on treatment. In PPS, the pCR (ypT0/is ypN0) rate was 71.43% (15/21). For different target lesions, 15 patients achieved ypT0/Tis (pCR rate = 71.43%) and 20 reached ypN0 (pCR rate = 95.24%). When stratified by CPS, pCR (ypT0/is ypN0) rate were 68.4%,72.2% and 76.9% in CPS ≥ 1, CPS ≥ 5 and CPS ≥ 10 subgroups, respectively. The ORR in PPS was 90.48% (n = 19/21, 95% CI: 68.18 - 98.33) and DCR reached 95.24% (n = 20/21, 95% CI: 74.13 - 99.75), including 9 complete response and 10 partial response. Treatment emergent adverse event (TEAE) occurred in 74.4% patients (32/43), of which 69.8% were Immune-related adverse event (irAE) (30/43). Grade ≥ 3 IrAE was 7.0% (3/43) and no treatment-related deaths were found. Conclusions: Combining tislelizumab and neoadjuvant nab-P-EC achieved favorable efficacy in TNBC, supporting that platinum-free regimen was non-inferior as a chemo-backbone. For heterogeneity of efficacy to immunotherapy, metastatic tumors in lymph nodes responded better to tislelizumab than primary tumor, suggesting that node-positive patients were potentially dominant population of neoadjuvant immunotherapy. Further results from the ongoing TREND trial and subsequent analysis of mechanism are urgently awaited. Clinical trial information: ChiCTR2000035262 .
Factors associated with severe immune checkpoint inhibitor-induced pneumonitis.
Authors: Hamzah Abu-Sbeih, Meghana Moodabagil, Jing Peng, Jianing Ma, Robert Easterling, Matthew Viveiros, Mingjia Li, Austin Secor, Evelyn Goodyear, Kari Lynn Kendra, Gregory Alan Otterson, Carolyn J Presley, Edwin Donnelly, Alexa Simon Meara, Dwight Hall Owen, Kevin Ho
Journal: Journal of Clinical Oncology (2023)

2658 Background: Immune checkpoint inhibitor (ICI) induced pneumonitis (ICIp) can be severe and even fatal, but risk factors for severe ICIp remain poorly characterized. In this abstract, we characterize ICIp and assess factors associated with severe disease. Methods: This is a retrospective study of consecutive patients who received ICI therapy and developed ICIp at the Ohio State University (2013-2020). Patients with ICIp were identified from a pharmacy database using ICD-10 codes followed by chart review to confirm diagnosis. ICIp was graded based on the CTCAE v5.0 criteria. Laboratory values were collected at the onset of ICIp. A thoracic radiologist reviewed chest imaging for pattern and severity. Survival probabilities were estimated with Kaplan-Meier curve and compared with log rank test. Results: Of 2963 patients who received ICI, we identified 119 patients (4%) with ICIp: 75 (63%) were males; 79 (66%) received PD-1 inhibitor monotherapy; and 71 (60%) had lung cancer. ICIp was severe (grade 1-2) in 69 patients (58%) and mild (grade 3-5) in 50 (42%). 74 patients (62%) were hospitalized. 63 patients (53%) needed oxygen supplementation. ICI therapy was held in all patients except one. ICI was rechallenged in 26 patients; 6 of them (23%) had recurrence of ICIp symptoms. All but 2 patients received steroids for the treatment of ICIp. 10 patients received non-steroidal medications (7 IVIG, 2 infliximab, 1 rituximab, 1 abatacept, 1 cyclophosphamide). Steroids were tapered in 6 patients of those who received non-steroidal medications. 3 of the patients who received IVIG had improvement of symptoms. Factors associated with severe ICIp. 21 patients (18%) died while hospitalized for ICIp are shown. Patients with severe ICIp had shorter overall survival than those with mild ICIp (P &lt; 0.001). Conclusions: ICIp is a serious adverse event that limits ICI treatment and can lead to hospitalization and death. Factors associated with severe ICIp in our study include lower lymphocyte and eosinophil counts, lower albumin levels, finding of consolidation or bronchiectasis on imaging, and lower predicted FVC and TLC. Prospective studies are merited to validate our findings and to investigate the appropriate treatment of ICIp. [Table: see text]
Phase II trial of XmAb20717 (vudalimab) in patients with advanced biliary tract cancers.
Authors: William Joseph Chapin, Parul Agarwal, Lisa DiCicco, Rayleigh Palmer, Nadia Cenou, Alexander Chan Chi Huang, Thomas Benjamin Karasic
Journal: Journal of Clinical Oncology (2023)

TPS4184 Background: For patients with advanced biliary tract cancers (BTCs), gemcitabine and cisplatin has been the standard-of-care first-line therapy, with a median overall survival (OS) of 11.7 months. More recently, TOPAZ-1 demonstrated a modest, but significant overall survival benefit (HR 0.80; 95% CI 0.66 – 0.97) to the addition of durvalumab to gemcitabine and cisplatin with a median OS of 12.8 months. However, for patients without targetable molecular variants, second-line and beyond options are limited, with FOLFOX demonstrating an overall response rate (ORR) of 5% and increase in median overall survival by 0.9 months compared to active symptom control. In patients with advanced BTCs, combination immunotherapy approaches with PD-1 or PD-L1 plus CTLA-4 inhibitors have been associated with improved ORRs of 10.8% - 23% compared to ORRs of 3 – 7% observed with single agent PD-1 or PD-L1 inhibitors. XmAb20717 (vudalimab) is a novel, bispecific antibody targeting PD-1 and CTLA-4 which demonstrated an ORR of 14.1% in a phase I dose expansion cohort of patients with advanced malignancies, including patients that had experienced disease progression on prior immune checkpoint inhibitors. Methods: We initiated a single-arm, phase II clinical trial with a Simon two-stage mini-max design to evaluate the efficacy of XmAb20717, in terms of ORR, in patients with advanced biliary tract cancers previously treated with gemcitabine-based chemotherapy. In the first stage, 13 patients evaluable for efficacy will be accrued. If no responses are observed in these 13 patients, the study will be stopped for futility. Otherwise, 14 additional patients evaluable for efficacy will be accrued to total 27 evaluable patients. If 4 or more responses are observed in these 27 patients, then the null hypothesis will be rejected. XmAb20717 (10 mg/kg) is administered intravenously on days 1 and 15 of a 28-day cycle. Important inclusion criteria include that patients with FGFR2 fusions, NTRK fusions, or IDH1 mutations must have received molecularly targeted therapy unless contraindicated or refused. Patients are not eligible if they have received prior immune checkpoint inhibitor therapy. Correlative studies will include longitudinal peripheral blood collection for circulating immune cell profiling. As of January, 2023, 8 patients have been enrolled with enrollment ongoing. Clinical trial information: NCT05297903 .
Comprehensive genomic landscape in pancreatic cancer using whole-exome sequencing.
Authors: Yonggang He, Xiaobing Huang, Lu Zheng, Wen Huang, Yichen Tang, Xuehui Peng, Jing Li, Jing Wu, Nan You, Chuang Liu, Yaxuan Zhang, Ling Li
Journal: Journal of Clinical Oncology (2023)

e16307 Background: Pancreatic ductal adenocarcinoma is one of the fatal malignancies in the world, mostly as a result of the absence of early detection and specific treatment solutions. Consequently, identifying mutational profiles and molecular biomarker are essential for increasing the viability of precision therapy for pancreatic cancer. Methods: We gathered blood and tumour tissue samples from 47 Chinese pancreatic cancer patients and used whole-exome sequencing (WES) to evaluate the genetic landscape. Results: Our results showed the most frequently somatic alteration genes were KRAS (74.5%), TP53 (51.1%), SMAD4 (17%), ARID1A (12.8%), CDKN2A (12.8%), TENM4 (10.6%), TTN (8.5%), RNF43 (8.5%), FLG (8.5%) and GAS6 (6.4%) in Chinese pancreatic ductal adenocarcinoma patients. We also found that three deleterious germline mutations ( ATM c.4852C &gt; T/p. R1618*, WRN c.1105C &gt; T/p. R369*, PALB2 c.2760dupA/p. Q921Tfs*7) and two novel fusions ( BRCA1-RPRML, MIR943 (intergenic)- FGFR3). When compared to the Cancer Genome Atlas (TCGA) database, there is a greater mutation frequency of TENM4 (10.6% vs. 1.6%, p= 0.01), GAS6 (6.4% vs. 0.5%, p= 0.035), MMP17 (6.4% vs. 0.5%, p= 0.035), ITM2B (6.4% vs. 0.5%, p= 0.035) and USP7 (6.4% vs. 0.5%, p= 0.035) as well as a reduced mutation frequency of SMAD4 (17.0% vs. 31.5%, p= 0.075) and CDKN2A (12.8% vs. 47.3%, p&lt; 0.001) were observed in the Chinese cohort. Among the 41 individual examined for PD-L1 expression, 15 (36.6%) had positive PD-L1 expression. The median tumour mutational burden (TMB) was found to be 12 muts (range, 0-124). The TMB index was higher in patients with mutant-type KRAS MUT/ TP53 MUT ( p&lt; 0.001), CDKN2A ( p= 0.547), or SMAD4 ( p= 0.064) compared to patients with wild-type KRAS/ TP53, CDKN2A, or SMAD4. Conclusions: We exhibited real-world genetic traits and new alterations in Chinese individuals with cancer of pancreas, which might have interesting implications for future individualized therapy and medication development.
A first-in-human pharmacodynamic evaluation of dual polyamine depletion for patients with high-grade gliomas.
Authors: Cecile Riviere-Cazaux, Bryan Neth, Sani Haider Kizilbash, Terry C Burns
Journal: Journal of Clinical Oncology (2023)

TPS2082 Background: No drug has improved survival for patients with high-grade gliomas (HGGs) since temozolomide in 2005. Relatively little is known about the live response of in situ gliomas to therapeutic intervention. Phase 0 studies that leverage access to the live human glioma in situ, including via microdialysis to sample the live glioma microenvironment, provide an attractive and feasible solution to this problem. We performed intraoperative microdialysis to evaluate the extracellular metabolome of divergent regions in 15 HGG resections. Our data revealed a conserved metabolic signature of HGGs and a novel glioma-associated metabolite, guanidinoacetate (GAA). Pathways enriched in this tumor signature included methionine and polyamine metabolism. Although GAA is typically converted to creatine, we hypothesize that the high flux of ornithine through ornithine decarboxylase (ODC) results in excess GAA accumulation. As such, in a Phase 0 trial, we will evaluate in situ glioma responses to polyamine depletion via ODC inhibition (Difluoromethylornithine, DFMO), with or without blockade of polyamine uptake (AMXT 1501), to identify candidate extracellular biomarkers of target engagement and cytotoxicity. Methods: Patients will be recruited who are undergoing a clinically indicated subtotal resection for a known or suspected high-grade glioma (NCT05717153). At the end of the surgery, two microdialysis catheters will be implanted for post-operative microdialysis, one in residual tumor and one in brain adjacent to tumor for an internal control. Beginning on post-operative day (POD) 1, patients will be randomized to one of the following three groups, including administration of vehicle, DFMO (500 mg, PO, BID) and AMXT 1501 (600 mg, PO, BID): 1) DFMO + AMXT 1501 (POD1-5); 2) Vehicle (POD1–POD2), followed by DFMO + AMXT 1501 (POD3-POD5); 3) DFMO alone (POD1–POD2), followed by DFMO + AMXT 1501 (POD3- POD5). Throughout this time, extracellular metabolite levels of polyamines, guanidinoacetate, and glutamate will be quantified from microdialysate collected every two hours from intraoperatively implanted 100 kDA microdialysis catheters. The primary outcome of this study is to determine how polyamine depletion impacts extracellular intratumoral guanidinoacetate abundance. The secondary outcomes of this study are to (1) determine the impact of polyamine depletion on polyamine abundance and the global extracellular metabolome within live human gliomas, in situ, and (2) assess the feasibility of longitudinal microdialysis for pharmacodynamic analysis within live human gliomas in situ in the post-operative setting. Clinical trial information: NCT05717153 .
Efficacy and safety study of a novel alpha-fetoprotein (AFP)-maytansine conjugate in an ovarian xenograft model.
Authors: Igor A. Sherman, Wendy Hill, Patricia Griffin, David Andrews, Rebecca J Boohaker, Karr Stinson, Lilian Tran Gien, Alla Buzina, Wiebke Schormann
Journal: Journal of Clinical Oncology (2023)

e14570 Background: AFP receptor is an oncofetal antigen and a novel target for cancer therapeutics. It is highly expressed on the surfaces of many cancers and Myeloid Derived Suppressor Cells (MDSCs) but absent on normal tissues. By conjugating maytansine toxin to a recombinant human AFP, we selectively deliver toxin to cancer cells and MDSCs while sparing normal cells, enabling a combination of targeted and immune activating approaches. We previously reported high efficacy of AFP-maytansine conjugate in a xenograft model of colorectal cancer. Here we report the effect of this conjugate in an ovarian xenograft model and in 2 independent patient-derived 3D ovarian organoids, supporting the wider utility of this approach. Methods: Four dose regimens of AFP-maytansine conjugate were compared to control in a mouse A2780 ovarian xenograft model. The conjugate was administered IV 10 days after implantation, when tumor volumes reached ≈150 mm 3 . Mice were randomized into 4 treatment and 1 control group (10 mice/group, table below). Tumor growth, survival and clinical observations were assessed for 62 days post implantation. In addition, organoids were cultured from primary reprogrammed tumor cells from 2 separate patients with high-grade serous ovarian carcinoma. Conjugate, staurosporine, thapsigargin or DMSO (control) were added to the media. Cytotoxicity was assessed by staining for AnnexinV and TMRE. Results: A statistically significant dose-dependent reduction in tumor volume (p&lt;0.001) and increase in survival (p&lt;0.002) were seen in all treatment groups relative to control. All animals in Groups 1,3 and 4 survived to the end of the study and 6 of 10 mice survived in the lowest dose group. 100% of mice in Group 1, highest dose group had complete tumor regression with no regrowth seen by day 62. In the other treatment groups majority of animals had complete tumor regression with no regrowth. All control animals were dead by day 38 due to excessive tumor burden. No signs of toxicity, such as ocular toxicity or vascular scarring of the tail were seen. All mice gained weight during the study. Gross pathology at the time of sacrifice was unremarkable. In addition, in the 2 ovarian organoids the AFP-maytansine conjugate demonstrated a cytotoxic effect over 72 hours exposure similar to that of thapsigargin and staurosporine given at known effective concentrations. Conclusions: This ovarian xenograft study confirms high activity without obvious toxicity of the novel AFP-maytansine conjugate in a 2nd tumor type. The targeted cytotoxic activity is further confirmed by the effect of the conjugate in 2 different ovarian cancer organoids. These results support advancing this novel conjugate toward clinical use with a dose-dense regimen. [Table: see text]